US4910225A - Locally administrable therapeutic composition for inflammatory disease - Google Patents
Locally administrable therapeutic composition for inflammatory disease Download PDFInfo
- Publication number
- US4910225A US4910225A US07/301,033 US30103389A US4910225A US 4910225 A US4910225 A US 4910225A US 30103389 A US30103389 A US 30103389A US 4910225 A US4910225 A US 4910225A
- Authority
- US
- United States
- Prior art keywords
- sup
- eye
- inflammatory
- acid
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- This invention relates to a locally administrable therapeutic composition for inflammatory eye disease as well as nasal or otic inflammatory disease.
- a locally administrable therapeutic composition for inflammatory eye as well as for nasal or otic inflammatory disease which contains as active ingredient a benzoylphenylacetic acid derivative, a salt thereof or the hydrate of said acid or salt.
- the other object of the present invention is to provide a stable locally administrable aqueous composition such as eye drop, otic composition and nasal composition containing the above compounds.
- steroid drugs such as dexamethazone have so far been employed.
- Topical application of steroid drugs to the eye has some apprehension of increasing intraocular pressure to cause glaucoma.
- corneal perforation when such steroid drugs are applied to patients suffered from corneal herpes, corneal ulcer or the like, but also of induction of corneal herpes, keratomycosis, Pseudomonas infections and the like by the topical application of steroid drugs.
- the present inventors investigated to find out topically applicable drugs with lesser side-effects and with superior effectiveness by which topically applicable drugs having been employed in the treatment of inflammatory ophthalmopathy, i.e. steroid anti-inflammatory agent, can be replaced.
- topically applicable drugs i.e. steroid anti-inflammatory agent
- the present inventors unexpectedly found that certain derivatives of benzoylphenylacetic acid are very effective in the treatment of inflammatory ophthalmopathy, especially of uveitis, by topical application, and that the effectiveness of such drugs is compatible with that of conventional steroid anti-inflammatory drugs.
- the inventors obtained the finding that there are some problems that the above-mentioned benzoylphenylacetic acid derivatives are unstable in an aqueous solution with the optimal pH range for a locally administrable therapeutic composition, they extensively investigated in search of the method for the preparation of a stable aqueous solution. As a result, we have succeeded in preparing a stable aqueous composition.
- the stable aqueous composition according to the invention are achieved based on the above finding.
- the other object of the invention is to provide a sufficiently stable aqueous solution such as eye drops, otic solution and nasal solution which contains the above compounds when stored for a long period of time.
- the present invention which has been completed based on the above finding, provides a therapeutic composition for administration to the eye for the treatment of inflammatory eye diseases which contains as active ingredient a benzoylphenylacetic acid of the formula ##STR2## [wherein R is a hydrogen or halogen atom], or salt thereof, or the hydrate of said acid or salt.
- the halogen atom represented by R is, for example, fluorine, chlorine, bromine or iodine.
- the above compound to be used in accordance with the invention may be in a salt form.
- the salt includes alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, among others, and any salt may suitably be used provided that it can attain the object of the invention.
- alkali metal salts such as sodium salt and potassium salt
- alkaline earth metal salts such as calcium salt and magnesium salt, among others
- any salt may suitably be used provided that it can attain the object of the invention.
- the compounds defined above may be obtained in the form of a hydrate depending on the conditions of synthesis, recrystallization and so forth, and such form may be used in practicing the invention without any inconvenience or trouble.
- the above compounds may be unstable when stored in an aqueous solution for a long period of time, and there are some problems in the stability of an aqueous solution containing the compounds. Therefore the inventors extensively investigated the stabilizing method in order to enhance the stability. As a result, unexpectedly, they have succeeded in stabilizing the solution by incorporating a water-soluble polymer and sulfite and adjusting the pH to about 6-9.
- the compounds to be used as active ingredients in the topically administrable therapeutic compositions for inflammatory eye disease as well as nasal or otic disease in accordance with the invention can be produced as described in the above-cited report in Journal of Medicinal Chemistry, Volume 27, pages 1379-1388 (1984) or U.S. Pat. No. 4,045,576, for instance, or by a modification of the method described therein.
- the ophthalmic compositions according to the invention can be prepared in the form of eye drops, eye ointments and so on in the same manner as various known compositions for topical administration to the eye.
- a compound of the above formula or a mixture of two or more compounds of the above formula is preferably made up into an aqueous or non-aqueous solution or mixed with an ointment base suited for ophthalmic use.
- an aqueous base generally used in the production of ophthalmic preparations, for example sterile distilled water, is suitably used as the aqueous base and the pH thereof is adjusted to a level suited for topical administration to the eye. It is desirable that an appropriate buffer should be added in adjusting the pH.
- the pH of the ophthalmic compositions according to the invention is selected with due consideration paid to the stability and topical eye irritativity of the active ingredient, among others.
- a water-soluble polymer includes polyvinyl pyrrolidone, carboxypropylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, sodium salt of polyacrylic acid an so on. Polyvinyl pyrrolidone is preferred among them.
- concentration of a water-soluble polymer is in the range of about 0.1 to 10 w/w%.
- Sulfite includes sodium, potassium, magnesium, calcium salt and so on.
- the concentration of sulfite is in the range of about 0.1 to 1.0 w/w %.
- the pH adjustment is generally conducted with sodium hydroxide or hydrochloric acid, for instance, and it is advisable to form a buffer solution by combined use of, for example, sodium acetate, sodium borate or sodium phosphate and acetic acid, boric acid or phosphoric acid, respectively.
- the ophthalmic compositions according to the invention may further contain pharmaceutically active ingredients, such as an anti-inflammatory agent of another kind, an analgesic and an antimicrobial, unless they are unfit for the purpose of attaining the object of the invention. Examples of such antiinflammatory agent are indomethacin and pranoprofen.
- the antimicrobial agents are penicillins, cephalosporins, and synthetic antimicrobial agents of the quinolonecarboxylic acid series.
- the anti-inflammatory agent is expected to be synergistic with said active ingredient in the ophthalmic compositions according to the invention.
- the analgestic is suited for the purpose of alleviating inflammation-associated pain
- the antimicrobial agent is suited for the purpose of preventing secondary infection. It is of course possible to incorporate active agents other than those mentioned above in the ophthalmic compositions according to the invention unless the object of the invention cannot be attained due to the presence thereof.
- an isotonizing agent in preparing the ophthalmic compositions according to the invention as mentioned above, an isotonizing agent, a microbicidal agent or preservative, a chelating agent, a thickening agent and so forth may be added to the compositions in accordance with the general practice of ophthalmic preparation manufacture.
- the isotonizing agent includes, among others, sorbitol, glycerine, polyethylene glycol, propylene glycol, glucose and sodium chloride.
- the preservative includes para-oxybenzoic acid esters, benzyl alcohol, parachloro-meta-xylenol, chlorocresol, phenetyl alcohol, sorbic acid and salts thereof, thimerosal, chlorobutanol, and the like.
- the chelating agent is, for example, sodium edetate, sodium citrate or sodium salt of condensed phosphoric acid.
- the ointment base can be selected from among petrolatum, Macrogol, carboxymethylcellulose sodium, etc.
- the ophthalmic composition according to this invention is prepared by incorporating the active compound in a base or vehicle for topical application to the eye.
- the concentration of the active ingredient may range from about 0.001% to about 10% and is preferably in the range of about 0.01% to about 5%.
- An ointment may be prepared by using the active compound in a concentration from about 0.001% to about 10%, preferably about 0.01% to about 5%.
- the ophthalmic composition of this invention may be administered in accordance with the following schedules. In the form of eye-drops, one to several drops per dose are instilled with a frequency of once to 4 times a day according to the clinical condition. Of course, the dosage may be adjusted according to symptoms.
- the ophthalmic composition according to this invention can be used topically for the treatment of inflammatory diseases of the eye without causing local irritant effects and produces beneficial effects surpassing those obtainable with the conventional drugs of the same type.
- a stable aqueous composition such as otic composition or nasal composition.
- Other conventional methods can be used unless unsuitable for the object of this invention.
- an isotonizing agent, buffer solution and preservatives can be used.
- concentrations of the compounds of the invention varies depending on symptoms and so on, and usually may be in the range of about 0.001 to about 10%, preferably about 0.01 to about 5%.
- Compound [I] Sodium 3-(4-bromobenzoyl)-2-aminophenylacetate monohydrate (hereafter referred to as Compound [I] was used as 0.5% and 0.1% ophthalmic solutions. These ophthalmic solutions had a pH value of 8.11 and osmolarities of 310 mOsm/kg ⁇ H 2 O and 325 mOsm/kg ⁇ H 2 O, respectively.
- Bovine serum albumin hereafter referred to as "BSA” was dissolved in physiological saline to a concentration of 5% and sterilized by filtration.
- ophthalmitis I A 0.1 ml portion of the solution was injected into the central part of the vitreus of both eyes using a 27G needle under anesthesia with 0.4% oxybuprocaine hydrochloride to induce ophthalmitis (ophthalmitis I). After 28 days when ophthalmitis I had nearly recovered, 2.5% BSA solution was administered in a dose of 25 mg/ml/kg into the auricular vein to cause ophthalmitis (ophthalmitis II). The severity of ophthalmitis was rated according to the rating scale.sup.(1) of Yamauchi et al., based on the Draize method in which an increased weight given to the internal segment of the eye.
- Table 1 shows the sum of scores for respective parameters during a peak inflammatory period of 3 days after aseptic injection of 5% BSA into the central part of the vitreous.
- Table 2 shows the amount of protein, white blood cell count and the concentration of prostaglandins in the anterior chamber aqueous humor.
- Compound [I] at concentrations of 0.1% and 0.5% caused a potent and dose-dependent inhibition for both the external and the internal segment of the eye. Furthermore, at both concentration levels, Compound [I] produced a substantially complete inhibition of prostaglandins in the aqueous humor in ophthalmitis I.
- the Compound [I] according to this invention produced a substantially complete inhibition at both concentrations.
- all drugs produced nearly the same degree of inhibition in both the internal and the external segments of the eye.
- each animal was sacrificed by cervical dislocation and in accordance with the method of Maistrello et al..sup.(2), the scalp was peeled off toward the eyelid and the edematous portion together with the skin was removed along the lid margin and weighed.
- the degrees of inhibition of carrageenin edema in the control group and drug treatment group are shown in Table 5.
- Each drug group showed a significant difference from the control group, indicating the effectiveness of the three compounds against acute ocular inflammation.
- Experiment 3.a in which the effect of Compound [I] was evaluated
- Experiment 3.b in which indomethacin, the most known anti-inflammatory drug with strong cyclooxgenase inhibitory activity, was evaluated.
- the inventors obtained the finding that by further incoporating sodium sulfite other than polyvinyl pyrrolidone, the stability was remarkably increased.
- the above ingredients are made up into an ophthalmic solution (the total volume being 100 ml) and pH is adjusted to 8.0.
- the above ingredients are made up into an ophthalmic solution (the total volume being 100 ml) and pH is adjusted to 8.0.
- the above ingredients are mixed up into an eye ointment (100 g) in the conventional manner.
- the above ingredients are mixed up in the conventional manner to give 100 g of an eye ointment.
- the above ingredients are made up into an ophthalmic solution (the total volume being 100 ml) and the pH is adjusted to 7.5 with hydrochloric acid.
- Table 11 are the residue and appearance of the compositions in Examples 6-8 after 4 weeks at 60° C.
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Ophthalmology & Optometry (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
This invention relates to a locally administrable therapeutic composition for inflammatory disease which is characterized by comprising benzoylphenylacetic acid of the formula ##STR1## (wherein R is a hydrogen or halogen atom), or a salt thereof, or the hydrate of said acid or salt, as active ingredient.
An ophthalmic composition according to the invention can treat effectively inflammatory eye disease by topical application, is not an irritant to the eye, and has a superior effect to conventional drugs of the same or similar type.
The aqueous composition prepared in accordance with this invention has excellent stability and can be used advantageously as a nasal or otic composition as well as an ophthalmic one in the treatment of inflammatory otic or nasal disease.
Description
1. Field of the Invention
This invention relates to a locally administrable therapeutic composition for inflammatory eye disease as well as nasal or otic inflammatory disease.
More particularly, it relates to a locally administrable therapeutic composition for inflammatory eye as well as for nasal or otic inflammatory disease, which contains as active ingredient a benzoylphenylacetic acid derivative, a salt thereof or the hydrate of said acid or salt.
The other object of the present invention is to provide a stable locally administrable aqueous composition such as eye drop, otic composition and nasal composition containing the above compounds.
2. Description of the Prior Art
That certain benzoylphenylacetic acid derivatives, when orally administered, exhibit anti-inflammatory activity has been reported in detail in Journal of Medicinal Chemistry, Volume 27, pages 1379-1388 (1984), among others. Furthermore, Japanese Laid Open Patent Publication No. 126124/1987 describes pharmaceutical compositions for percutaneous administration which contain these compounds. However, none of the published literature-inclusive of the above-mentioned patent specification-contains any description indicating or suggesting that these medicinal substances are effective against inflammatory disease of the eye, nose or ear when they are administered topically.
For the treatment, with topical application of drugs, of inflammatory ophthalmopathy such as uveitis and conjunctivitis which are most frequently observed in the ophthalmological field, steroid drugs such as dexamethazone have so far been employed. Topical application of steroid drugs to the eye has some apprehension of increasing intraocular pressure to cause glaucoma. And, there is a fear not only of causing corneal perforation when such steroid drugs are applied to patients suffered from corneal herpes, corneal ulcer or the like, but also of induction of corneal herpes, keratomycosis, Pseudomonas infections and the like by the topical application of steroid drugs. As there has been known such-effects as above, steroid anti-inflammatory agents shall be applied with particular care. In spite of such a situation, there has not been known any non-steroid anti-inflammatory agent compatible with steroid anti-inflammatory drugs in effectiveness for the treatment of inflammatory opthalmopathy such as uveitis. Thus, in the present stage in this technical field, for the treatment of inflammatory ophthalmopathy, it is hardly possible not to use steroid anti-inflammatory agents with particular care to avoid the side effects as above-mentioned. Under such circumstances, it is natural that ophthalmological experts are awaiting the appearance of non-steroid drugs which are effectively usable against uveitis or the like.
The present inventors investigated to find out topically applicable drugs with lesser side-effects and with superior effectiveness by which topically applicable drugs having been employed in the treatment of inflammatory ophthalmopathy, i.e. steroid anti-inflammatory agent, can be replaced. As a result, the present inventors unexpectedly found that certain derivatives of benzoylphenylacetic acid are very effective in the treatment of inflammatory ophthalmopathy, especially of uveitis, by topical application, and that the effectiveness of such drugs is compatible with that of conventional steroid anti-inflammatory drugs.
Furthermore, since the inventors obtained the finding that there are some problems that the above-mentioned benzoylphenylacetic acid derivatives are unstable in an aqueous solution with the optimal pH range for a locally administrable therapeutic composition, they extensively investigated in search of the method for the preparation of a stable aqueous solution. As a result, we have succeeded in preparing a stable aqueous composition. Thus, the stable aqueous composition according to the invention are achieved based on the above finding.
While a number of non-steroid compounds fall under the category of anti-inflammatory agents, all of them are not effective in treating inflammatory eye diseases when topically administered to the eye. This is because there are several problems lying before them. First, when topically administered to the eye, a medicinal agent has to pass through the cornea so that it can reach the site of inflammation. Even when it has succeeded in arriving at the site of inflammation, it must remain there in a necessary concentration for a necessary period of time. If it fails to meet these requirements, it will be unable to produce expected therapeutic effects. Furthermore, in case it is irritative to the eye, it is rather possible that the topical administration of the medicinal agent to the eye would cause exacerbation of symptoms. Therefore, great caution and much care are necessary in selecting a medicinal agent for topical administration to the eye. Furthermore, in case of administration in the form of eye drops, it goes without saying that it is desirable that the eye drop is stable for a long period of time in an aqueous solution without decomposition or forming insoluble matters.
Accordingly, it is an object of the invention to solve the above problems and provide a novel and useful agent for ophthalmic use.
Moreover, the other object of the invention is to provide a sufficiently stable aqueous solution such as eye drops, otic solution and nasal solution which contains the above compounds when stored for a long period of time.
The present invention, which has been completed based on the above finding, provides a therapeutic composition for administration to the eye for the treatment of inflammatory eye diseases which contains as active ingredient a benzoylphenylacetic acid of the formula ##STR2## [wherein R is a hydrogen or halogen atom], or salt thereof, or the hydrate of said acid or salt. In the formula, the halogen atom represented by R is, for example, fluorine, chlorine, bromine or iodine. The above compound to be used in accordance with the invention may be in a salt form. The salt includes alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, among others, and any salt may suitably be used provided that it can attain the object of the invention. The compounds defined above may be obtained in the form of a hydrate depending on the conditions of synthesis, recrystallization and so forth, and such form may be used in practicing the invention without any inconvenience or trouble.
Further, the above compounds may be unstable when stored in an aqueous solution for a long period of time, and there are some problems in the stability of an aqueous solution containing the compounds. Therefore the inventors extensively investigated the stabilizing method in order to enhance the stability. As a result, unexpectedly, they have succeeded in stabilizing the solution by incorporating a water-soluble polymer and sulfite and adjusting the pH to about 6-9.
The compounds to be used as active ingredients in the topically administrable therapeutic compositions for inflammatory eye disease as well as nasal or otic disease in accordance with the invention (although such compositions are occasionally hereinafter referred to as "opthalmic composition according to the present invention", use of this abbreviation does not exclude the application of the composition in the nasal or otic fields) can be produced as described in the above-cited report in Journal of Medicinal Chemistry, Volume 27, pages 1379-1388 (1984) or U.S. Pat. No. 4,045,576, for instance, or by a modification of the method described therein. The ophthalmic compositions according to the invention can be prepared in the form of eye drops, eye ointments and so on in the same manner as various known compositions for topical administration to the eye. Thus, a compound of the above formula or a mixture of two or more compounds of the above formula is preferably made up into an aqueous or non-aqueous solution or mixed with an ointment base suited for ophthalmic use. On that occasion, an aqueous base generally used in the production of ophthalmic preparations, for example sterile distilled water, is suitably used as the aqueous base and the pH thereof is adjusted to a level suited for topical administration to the eye. It is desirable that an appropriate buffer should be added in adjusting the pH. The pH of the ophthalmic compositions according to the invention is selected with due consideration paid to the stability and topical eye irritativity of the active ingredient, among others. According to the present invention, the stability of an aqueous composition containing the above compounds is remarkably enhanced by incorporating a water-soluble polymer and sulfite, and adjusting the pH to 6.0-9.0, preferably about 7.5-8.5. The eye irritation of the solution is not observed. A water-soluble polymer includes polyvinyl pyrrolidone, carboxypropylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, sodium salt of polyacrylic acid an so on. Polyvinyl pyrrolidone is preferred among them. The concentration of a water-soluble polymer is in the range of about 0.1 to 10 w/w%. Sulfite includes sodium, potassium, magnesium, calcium salt and so on. The concentration of sulfite is in the range of about 0.1 to 1.0 w/w %. The pH adjustment is generally conducted with sodium hydroxide or hydrochloric acid, for instance, and it is advisable to form a buffer solution by combined use of, for example, sodium acetate, sodium borate or sodium phosphate and acetic acid, boric acid or phosphoric acid, respectively. The ophthalmic compositions according to the invention may further contain pharmaceutically active ingredients, such as an anti-inflammatory agent of another kind, an analgesic and an antimicrobial, unless they are unfit for the purpose of attaining the object of the invention. Examples of such antiinflammatory agent are indomethacin and pranoprofen. Usable examples of the antimicrobial agents are penicillins, cephalosporins, and synthetic antimicrobial agents of the quinolonecarboxylic acid series. Among these active ingredients for combined use with the active ingredient according to the invention, the anti-inflammatory agent is expected to be synergistic with said active ingredient in the ophthalmic compositions according to the invention. The analgestic is suited for the purpose of alleviating inflammation-associated pain, and the antimicrobial agent is suited for the purpose of preventing secondary infection. It is of course possible to incorporate active agents other than those mentioned above in the ophthalmic compositions according to the invention unless the object of the invention cannot be attained due to the presence thereof.
In preparing the ophthalmic compositions according to the invention as mentioned above, an isotonizing agent, a microbicidal agent or preservative, a chelating agent, a thickening agent and so forth may be added to the compositions in accordance with the general practice of ophthalmic preparation manufacture. The isotonizing agent includes, among others, sorbitol, glycerine, polyethylene glycol, propylene glycol, glucose and sodium chloride. The preservative includes para-oxybenzoic acid esters, benzyl alcohol, parachloro-meta-xylenol, chlorocresol, phenetyl alcohol, sorbic acid and salts thereof, thimerosal, chlorobutanol, and the like. The chelating agent is, for example, sodium edetate, sodium citrate or sodium salt of condensed phosphoric acid. In preparing the ophthalmic compositions according to the invention in the form of eye ointments, the ointment base can be selected from among petrolatum, Macrogol, carboxymethylcellulose sodium, etc.
The ophthalmic composition according to this invention is prepared by incorporating the active compound in a base or vehicle for topical application to the eye. To prepare a liquid preparation, the concentration of the active ingredient may range from about 0.001% to about 10% and is preferably in the range of about 0.01% to about 5%. An ointment may be prepared by using the active compound in a concentration from about 0.001% to about 10%, preferably about 0.01% to about 5%. The ophthalmic composition of this invention may be administered in accordance with the following schedules. In the form of eye-drops, one to several drops per dose are instilled with a frequency of once to 4 times a day according to the clinical condition. Of course, the dosage may be adjusted according to symptoms. The ophthalmic composition according to this invention can be used topically for the treatment of inflammatory diseases of the eye without causing local irritant effects and produces beneficial effects surpassing those obtainable with the conventional drugs of the same type.
According to this invention, there can be obtained a stable aqueous composition such as otic composition or nasal composition. Other conventional methods can be used unless unsuitable for the object of this invention. Among others, an isotonizing agent, buffer solution and preservatives can be used. The concentrations of the compounds of the invention varies depending on symptoms and so on, and usually may be in the range of about 0.001 to about 10%, preferably about 0.01 to about 5%.
The following experimental examples are given to delineate the efficacy profile of the ophthalmic composition of this invention and the stability of the aqueous compositions of the invention.
Seventeen male white rabbits weighing about 2 kg were used. They were fed with 80 g of Labo RG-RO (Nippon Agricultural Co., Ltd.) daily and had free access to tap water.
Sodium 3-(4-bromobenzoyl)-2-aminophenylacetate monohydrate (hereafter referred to as Compound [I] was used as 0.5% and 0.1% ophthalmic solutions. These ophthalmic solutions had a pH value of 8.11 and osmolarities of 310 mOsm/kg·H2 O and 325 mOsm/kg·H2 O, respectively. Bovine serum albumin (hereafter referred to as "BSA") was dissolved in physiological saline to a concentration of 5% and sterilized by filtration. A 0.1 ml portion of the solution was injected into the central part of the vitreus of both eyes using a 27G needle under anesthesia with 0.4% oxybuprocaine hydrochloride to induce ophthalmitis (ophthalmitis I). After 28 days when ophthalmitis I had nearly recovered, 2.5% BSA solution was administered in a dose of 25 mg/ml/kg into the auricular vein to cause ophthalmitis (ophthalmitis II). The severity of ophthalmitis was rated according to the rating scale.sup.(1) of Yamauchi et al., based on the Draize method in which an increased weight given to the internal segment of the eye. Observation was made with a frequency of once in one or two days during the peak period of inflammation and once in three or four days before and after the peak period for ophthalmitis I and 3, 6, 12 and 24 hours after intravenous injection of BSA for ophthalmitis II.
Anti-inflammatory effect in ophthalmitis I
Table 1 shows the sum of scores for respective parameters during a peak inflammatory period of 3 days after aseptic injection of 5% BSA into the central part of the vitreous.
Table 2 shows the amount of protein, white blood cell count and the concentration of prostaglandins in the anterior chamber aqueous humor.
Anti-inflammatory effect in ophthalmitis II
The administration of 2.5 ml/kg of 2.5% BSA solution into the auricular vein after 29 days when the inflammatory symptoms of ophthalmitis I had substantially subsided resulted in a relapse of inflammation after 3 hours in the physiological saline group, where both the external and internal segment of the eye after 12 hours showed inflammatory pictures similar to those observed at the peak of ophthalmitis I. These symptoms were still observed even after 24 hours. Table 3 shows the scores for respective parameters at 3, 6, 12 and 24 hours after the intraveous injection of BSA. Table 4 shows the amount of protein, white blood cell count and the concentration of prostaglandins in the anterior chamber aqueous humor.
Administration of the test drug
Gross observation was made on the day after injection of BSA into the vitreous body and with the animals arranged in the decreasing order of severity of ocular inflammation, grouping was carried out in such a manner that the intensity distribution would be uniform over the groups. Thus, a physiological saline group of 7 animals, a 0.1% Compound [I] instillation group of 4 animals and a 0.5% Compound [I] instillation group of 5 animals were provided. After this grouping procedure, the test drugs and saline were respectively instilled into both eyes of the rabbits, 50 μl per dose, 4 times a day. For induction of ophthalmitis II, each drug was instilled into both eyes, 50 μl per dose, immediately after injection of BSA into the auricular vein and at 1-hour intervals thereafter, for a total of 14 times.
In ophthalmitis I, Compound [I] at concentrations of 0.1% and 0.5% caused a potent and dose-dependent inhibition for both the external and the internal segment of the eye. Furthermore, at both concentration levels, Compound [I] produced a substantially complete inhibition of prostaglandins in the aqueous humor in ophthalmitis I.
In regard to the inhibitory effect on inflammatory symptoms, as evaluated by gross observation, which are induced by the intraveous injection of antigen, the Compound [I] according to this invention produced a substantially complete inhibition at both concentrations. As to white blood cell count, all drugs produced nearly the same degree of inhibition in both the internal and the external segments of the eye.
For any of the drugs, no body weight suppression was observed even after 28 consecutive days of treatment. In the organs including the thymus, spleen, adrenal and so on, anatomically no abnormality was found.
1. Sodium 3-(4-bromobenzoyl)-2-aminophenyl-acetate (hereinafter referred to as Compound [I])
2. Sodium 3-(4-chlorobenzoyl)-2-aminophenyl-acetate (hereinafter referred to as Compound [II])
3. Sodium 3-benzoyl-2-aminophenylacetate (hereinafter referred to as Compound [III])
Using female Wister rates weighing 100 g in groups of 5 animals or 10 eyes, 0.05 ml of 1% carrageenin (dissolved in physiological saline at 50° C.) as a phlogogen was injected beneath the conjuctiva of both eyes to induce edema. Physiological saline, as a control, and test drugs were respectively instilled into both eyes 40 and 20 minutes before and immediately after the injection of carrageenin, in the amount of 2.5 μl per dose. Four hours after the phlogogen treatment, each animal was sacrificed by cervical dislocation and in accordance with the method of Maistrello et al..sup.(2), the scalp was peeled off toward the eyelid and the edematous portion together with the skin was removed along the lid margin and weighed. The degrees of inhibition of carrageenin edema in the control group and drug treatment group are shown in Table 5. Each drug group showed a significant difference from the control group, indicating the effectiveness of the three compounds against acute ocular inflammation.
The experiment was divided into two parts, i.e. Experiment 3.a, in which the effect of Compound [I] was evaluated, and Experiment 3.b, in which indomethacin, the most known anti-inflammatory drug with strong cyclooxgenase inhibitory activity, was evaluated.
The solutions of the following formulas were used.
______________________________________
a. Compound [I]
Compound [I] 0.1 0.01 0.001 0.0001%
Boric acid 1.0 1.0 1.0 1.0%
Borax q.s. q.s. q.s. q.s.
Sodium chloride
0.25 0.25 0.25 0.25%
Sodium edetate 0.02 0.02 0.02 0.02%
Benzalkonium chloride
0.005 0.005 0.005 0.005%
Tween 80 0.3 0.3 0.3 0.3%
(pH 8.0, Osmotic pressure 310 mOsm/Kg.H.sub.2 O)
b. Indomethacin
Indomethacin 0.5%
Castor oil q.s.
______________________________________
Totally 28 male albino rabbits (4 rabbits×7 groups) with a body weight of about 2 kg werr used. They had been confirmed, before the experiment, to have mydriatic response to 1% atropine for at least 4 hours.
50 μl each of 1% atropine solution was instilled into both eyes of the animals one hour before the 1st paracenthesis, in which approx. 0.2 ml/eye of aqueous humor (primary aqueous humor) was collected. Topical application of 50 μl each of the test drug solutions was conducted 30 min before the paracenthesis. Pupil diameter of each eye was measured with a slide caliper immediately before and 10 min after the paracenthesis. The 2nd paracenthesis was conducted 90 min after the 1st one, in which approx. 0.2 ml/eye of aqueous humor (secondary aqueous humor) was collected.
As shown in Table 6, Compound [I] exhibited a dose-related inhibitory activity on miosis after paracentesis at the concentrations of 0.0001-0.1%, whereas little effect was observed with indomethacin at the concentrations as high as 0.5%. As shown in Table 7, Compound [I] exhibited a strong and dose-related inhibitory activity on protein increase after paracenthesis, in which the effect of 0.01% of Compound [I] was equivalent to that of 0.5% indomethacin. It is well known that atropine-resistant miosis and protein increase in aqueous humor after paracentesis are caused by prostaglandin E2, which-is one of the most important chemical mediators of inflammation and is synthesized immediately after mechanical injury. The results, therefore, indicate that Compound [I] has stronger anti-inflammatory effect than indomethacin.
______________________________________
Formula
______________________________________
Compound [I] 0.1 g
Borax 1.0 g
Sodium borate Sufficient quantity
Sodium chloride 0.25 g
Disodium edetate 0.02 g
Benzalkonium chloride
0.005 g
Polysorbate 80 0.3 g
Sterile purified water
To make 100 ml
______________________________________
Stability was observed at 60° C. of the compound by changing pH (6.0, 7.0, 8.0 and 9.0) of the above formula. The results are shown in Table 8.
Of the above four, the formula at the pH of 8 is most stable. In the formula, the change in residue rate were not almost observed but in three weeks red insoluble matters were observed.
As a result of extensive examination on preventing the red insoluble matters, the stability was observed by incorporating polyvinyl pyrrolidone.
______________________________________
Formulas B-1 B-2
______________________________________
Compound [I] 0.1 g 0.1 g
Boric acid 1.5 g 1.5 g
Borax Sufficient quantity
Disodium edetate 0.02 g 0.02 g
Benzalkonium chloride
0.007 g 0.007
g
Polysorbate 80 0.15 g 0.15 g
Polyvinyl pyrrolidone
2.0 g --
Sterile purified water
To make 100 ml
pH 8 pH 8
______________________________________
In the above formulas, the results of the stability at 60° C. are as follows (Table 9):
It was found that by incorporating polyvinyl pyrrolidone, the appearance of red insoluble matters was considerably prevented. In four weeks, however, some insoluble matters were observed.
Moreover, as a result of searching for more stable solutions, the inventors obtained the finding that by further incoporating sodium sulfite other than polyvinyl pyrrolidone, the stability was remarkably increased.
______________________________________
Formulas B B-3
______________________________________
Compound [I] 0.1 g 0.1 g
Boric acid 1.5 g 1.5 g
Borax Sufficient quantity
Disodium edetate 0.02 g 0.02 g
Benzalkonium chloride
0.007 g 0.007
g
Polyvinyl pyrrolidone
0.15 g 0.15 g
Sodium sulfite -- 0.2 g
Sterile purified water
To make 100 ml
pH 8 pH 8
______________________________________
As shown in Table 10, the change of appearance was observed in the formula in which sodium sulfite was not incorporated, and the residue increased by about 7%. By contrast, In the solution containing Compound [I] in which polyvinyl pyrrolidone and sodium sulfite coexist, the change of appearance was not observed at all and the decomposition of Compound [I] was not observed either. It was found that the stability was remarkably enhanced. Thus, there can be successfully obtained a stable aqueous composition containing the compounds.
The following are explanatory examples of the ophthalmic composition and other stable aqueous compositions according to the invention.
______________________________________
Sodium 3-(4-Bromobenzoyl)-2-aminophenyl-
0.1%
acetate monohydrate
Boric acid 1.0%
Borax Sufficient quantity
Sodium chloride 0.25%
Sodium edetate 0.02%
Benzalkonium chloride 0.005%
Polysorbate 80 0.3%
Purified water Sufficient quantity
______________________________________
The above ingredients are made up into an ophthalmic solution (the total volume being 100 ml) and pH is adjusted to 8.0.
______________________________________
Sodium 3-benzoyl-2-amino-phenyl-
0.1%
acetate
Boric acid 1.0%
Borax 0.02%
Sodium chloride 0.25%
Sodium edetate Sufficient quantity
Benzalkonium chloride 0.005%
Polysorbate 80 0.3%
Purified water Sufficient quantity
______________________________________
The above ingredients are made up into an ophthalmic solution (the total volume being 100 ml) and pH is adjusted to 8.0.
______________________________________
Sodium 3-(4-chlorobenzoyl)-2-amino-
1.0%
phenylacetate
White petrolatum Sufficient quantity
______________________________________
The above ingredients are mixed up into an eye ointment (100 g) in the conventional manner.
______________________________________
Sodium 3-(4-chlorobenzoyl)-2-amino-
0.01 g
phenylacetate monohydrate
Carboxymethylcellulose
Sufficient quantity
______________________________________
The above ingredients are mixed up in the conventional manner to give 100 g of an eye ointment.
______________________________________
Sodium 3-(4-chlorobenzoyl)-2-amino-
1.0 g
phenylacetate monohydrate
Sodium chloride 0.8 g
Tween 80 0.2 g
Purified water Sufficient quantity
______________________________________
The above ingredients are made up into an ophthalmic solution (the total volume being 100 ml) and the pH is adjusted to 7.5 with hydrochloric acid.
______________________________________
Sodium 3-(4-bromobenzoyl)-2-aminophenyl-
0.1 g
acetate monohydrate
Boric acid 1.25 g
Borax 1.0 g
Disodium edetate 0.02 g
Benzalkonium chloride 0.005 g
Polysorbate 80 0.15 g
Polyvinyl pyrrolidone 2.0 g
Sodium sulfite 0.2 g
Sterile purified water To make 100 ml
pH 8
______________________________________
______________________________________
Sodium 3-(4-bromobenzoyl)-2-aminophenyl-
0.1 g
acetate monohydrate
Boric acid 0.7 g
Borax Sufficient quantity
Sodium chloride 0.5 g
Polysorbate 80 0.15 g
Methylparaben 0.013 g
Ethylparaben 0.007 g
Polyvinyl pyrrolidone 2.0 g
Sodium sulfite 0.2 g
Sodium edetate 0.02 g
Sterile purified water To make 100 ml
______________________________________
______________________________________
Sodium 3-(4-bromobenzoyl)-2-aminophenyl-
0.1 g
acetate monohydrate
Boric acid 1.5 g
Borax Sufficient quantity
Benzalkonium chloride 0.005 g
Polysorbate 80 0.15 g
Polyvinyl pyrrolidone 2.0 g
Sodium sulfite 0.1 g
Sterile purified water To make 100 ml
pH 8
______________________________________
The following (Table 11) are the residue and appearance of the compositions in Examples 6-8 after 4 weeks at 60° C.
As shown in Table 11, it was found that changes in appearances of the compositions were not observed at all, and the decomposition of the compound was not almost observed, the aqueous compositions being stable, excellent for a long period of time.
______________________________________
Sodium 3-(4-bromobenzoyl)-2-aminophenyl-
0.1 g
acetate monohydrate
Sodium monohydrogen phosphate
0.2 g
Sodium dihydrogen phosphate
Sufficient quantity
Sodium chloride 0.8 g
Benzalkonium chloride 0.007 g
Polysorbate 80 0.15 g
Polyvinyl alcohol 1.0 g
Potassium sulfite 0.2 g
Sterile purified water To make 100 ml
pH 8
______________________________________
______________________________________
Sodium 3-(4-bromobenzoyl)-2-aminophenyl-
0.1 g
acetate monohydrate
Boric acid 0.1 g
Borax Sufficient quantity
Sodium chloride 0.8 g
Methylparaben 0.3 g
Ethylparaben 0.1 g
Polyvinyl pyrrolidone 2.0 g
Sodium sulfite 0.1 g
Sterile purified water To make 100 ml
pH 7.5
______________________________________
TABLE 1
__________________________________________________________________________
Test Drug
Physiological
Compound [I]
Compound [I]
Parameter saline (14).sup.a
0.1% (8).sup.a
0.5% (10).sup.a
__________________________________________________________________________
External Segment
Corneal opacity
2.5 ± 0.5
1.0 ± 0.4 (60.0).sup.b
0.4 ± 0.2 *.sup.2 (48.0).sup.b
Palpebral cunjunctival
3.8 ± 0.5
1.3 ± 0.2 *.sup.2 (65.8).sup.b
1.5 ± 0.3 *.sup.2 (36.8).sup.b
injection
Palpebral conjunctival
0.7 ± 0.3
0.1 ± 0.1 (85.7).sup.b
0 *.sup.2 (100).sup.b
edema
Balbar conjunctival
6.5 ± 0.7
4.5 ± 0.6 (30.8).sup.b
1.6 ± 0.2 *.sup.1 (74.5).sup.b
injection
Discharge 0.3 ± 0.1
0 *.sup.1 (100).sup.b
0 *.sup.3 (100).sup.b
Total Score
13.7 ± 1.9
6.8 ± 1.0 *.sup.1 (50.4).sup.b
3.5 ± 0.4 *.sup.3 (74.5).sup.b
Internal Segment
Anterior chamber
3.0 ± 0.3
3.6 ± 0.8 (-20.0).sup.b
2.0 ± 0.4 (33.3).sup.b
opacity
Iridic injection
6.1 ± 0.6
2.6 ± 0.2 *.sup.3 (57.4).sup.b
1.8 ± 0.2 *.sup.3 (70.5).sup.b
Morphological
4.4 ± 0.2
2.9 ± 0.4 *.sup.2 (34.1).sup.b
2.9 ± 0.4 *.sup.2 (34.1).sup.b
change of iris
Total Score
13.5 ± 0.8
9.1 ± 1.0 *.sup.2 (32.6).sup.b
6.6 ± 0.8 *.sup.3 (51.1).sup.b
External + Internal
Grand Total Score
27.3 ± 2.5
15.9 ± 1.8 *.sup.2 (41.8).sup.b
10.1 ± 1.0 *.sup.3 (63.0).sup.b
__________________________________________________________________________
[Notes to Table 1
Each value represents the mean ± standard error. The figure in
parentheses.sup. a represents the number of cases, and the figure in
parentheses.sup. b represents the degree (%) of inhibition relative to th
physiological saline group. Significant differences from the physiologica
saline group at the levels of *.sup.1 = p < 0.05, *.sup.2 = p < 0.01 and
*.sup.3 = p < 0.001.
TABLE 2
__________________________________________________________________________
Concentration
Number
Protein
White Blood Cell
Prostaglandin
Drug % of Cases
mg/Mml Cells/mm.sup.3
ng/ml
__________________________________________________________________________
Physiological
-- 7 50.3 ± 7.3
5869 ± 2194
1.89 ± 0.75
saline
Compound [I]
0.1 4 48.7 ± 3.8
5593 ± 3436
<0.4.sup.a
0.5 5 28.4 ± 1.6*.sup.1
1980 ± 654
<0.4.sup.a
__________________________________________________________________________
[Notes to Table 2
Each value represents the mean ± standard error; .sup.a means that the
concentration is less than the assay limit (0.4 ng/ml); *.sup.1 means a
significant difference from the physiological saline group at p < 0.05.
TABLE 3
__________________________________________________________________________
Test Drug
Physiological
Compound [I]
Compound [I]
Parameter saline (14).sup.a
0.1% (8).sup.a
0.5% (10).sup.a
__________________________________________________________________________
1/10 External Segment
Corneal opacity
1.4 ± 0.3
0.6 ± 0.2 (57.1).sup.b
0.6 ± 0.2 (57.1).sup.b
Palpebral conjunctival
5.7 ± 0.7
4.0 ± 0.3 (29.8).sup.b
3.7 ± 0.1 *.sup.1 (60.5).sup.b
injection
Palpebral conjunctival
2.0 ± 0.8
1.1 ± 0.4 (45.0).sup.b
0.9 ± 0.2 (55.0).sup.b
edema
Balbar conjunctival
11.1 ± 0.6
8.1 ± 0.4 (27.0).sup.b
8.1 ± 0.3 *.sup.2 27.0).sup.b
injection
Discharge 0.3 ± 0.1
0 (100).sup.b
0 (100).sup.b
Total Score
20.5 ± 2.5
13.1 ± 1.1 *.sup.1 (32.7).sup.b
13.3 ± 0.6 *.sup.1 (31.4).sup.b
Internal Segment
Anterior chamber
1.9 ± 0.3
2.8 ± 0.8 (-47.4).sup.b
2.8 ± 0.5 (-47.4).sup.b
opacity
Iridic injection
7.3 ± 0.8
2.8 ± 0.1 *.sup.2 (61.6).sup.b
3.3 ± 0.3 *.sup.2 (54.8).sup.b
Morphological
4.3 ± 0.5
2.4 ± 0.4 *.sup.2 (44.2).sup.b
2.9 ± 0.3 *.sup.1 (32.6).sup.b
change of iris
Total Score
13.5 ± 1.1
8.0 ± 1.2 *.sup.2 (40.7).sup.b
9.0 ± 0.7 *.sup.2 (33.3).sup.b
External + Internal
Grand Total Score
33.9 ± 3.5
21.8 ± 2.1 *.sup.1 (35.7).sup.b
22.3 ± 1.1 *.sup.1 (34.2).sup.b
__________________________________________________________________________
[Notes to Table 3
Each value represenets the mean ± standard error. The figure in
parentheses .sup.a represents the number of cases, and the figure in
parentheses .sup.b represents the degree (%) of inhibition relative to th
physiological saline group. Significant differences from the physiologica
saline group at the levels of *.sup.1 = p < 0.05, and *.sup.2 = p < 0.01.
TABLE 4
__________________________________________________________________________
Concentration
Number
Protein
White Blood Cell
Prostaglandin
Drug % of Cases
mg/Mml Cells/mm.sup.3
ng/ml
__________________________________________________________________________
Physiological
-- 10 39.5 ± 2.20
2416 ± 478
15.79 ± 4.86
saline
Compound [I]
0.1 8 48.7 ± 3.8
1489 ± 499
<0.4.sup.a *.sup.1
0.5 10 28.4 ± 1.6*.sup.1
1673 ± 277
<0.4.sup.a *.sup.2
__________________________________________________________________________
[Notes to Table 4
Each value represents the mean ± standard error; .sup.a means that the
concentration is less than the assay limit (0.4 ng/ml); *.sup.1 means a
significant difference from the physiological saline group at the level o
*.sup.1 = p <0.05, and *.sup.2 = p <0.01.
TABLE 5
______________________________________
Weight of Degree of
Concentration
Edema* inhibition
Compound (%) (mg) (%)
______________________________________
Compound [I]
1.0 43.93 ± 4.138
16.9**
2.5 36.323 ± 3.308
31.3**
Compound [III]
1.0 30.98 ± 3.194
41.4**
5.0 32.80 ± 2.409
37.9**
Control -- 52.17 ± 2.401
--
Compound [II]
0.5 37.52 ± 2.423
36.9**
1.0 39.02 ± 3.057
34.4**
Control -- 59.47 ± 3.057
--
______________________________________
[Notes to Table 5
*Each value represents the mean ± standard error for 10 eyes.
**Significant differences from the control group at p<0.001.
TABLE 6
______________________________________
Test drug
Content (%)
Miosis (%) Inhibition (%)
______________________________________
Physiological
-- 23.7 ± 1.94
--
saline
Exp. 3, a
0.1 17.4 ± 3.80
24.9 ± 16.4
0.01 15.4 ± 1.60
*2 35.2 ± 6.75
0.001 19.0 ± 1.44
19.7 ± 6.08
0.0001 21.5 ± 1.97
9.2 ± 8.33
Physiological
-- 17.6 ± 1.88
--
saline
Indomethicin
0.5 16.4 ± 3.86
6.0 ± 21.4
______________________________________
t-test *2: P < 0.01
Table 7
__________________________________________________________________________
Primary aqueous
Secondary aqueous
Test humor humor Inhibition
drug Content (%)
Protein (μg/ml)
Protein (μg/ml)
(%)
__________________________________________________________________________
Physiological saline
0.89 ± 0.20
25.04 ± 4.12
--M -Exp. 3, b 0.1 0.76 ± 0.20
3.06 ± 0.46 *2 87.8
0.01 0.39 ± 0.04 *1
9.29 ± 7.30 *2
62.9
0.001 0.38 ± 0.02 *1
18.45 ± 3.53
26.3
0.0001 0.44 ± 0.06
23.45 ± 1.67
6.3
Physiological saline
0.84 ± 0.11
20.21 ± 1.79
--
Indomethacin
0.5 0.77 ± 0.10
6.13 ± 1.64 *3
69.7
__________________________________________________________________________
test *1: P < 0.05 *2: P < 0.01 *3: P < 0.001
TABLE 8 ______________________________________ Formula pH Appearance Residue (%) ______________________________________ 1 Week A-1 pH 6.0 + 38.6 2 pH 7.0 + 79.3 3 pH 8.0 - 100.5 4 pH 9.0 - 101.1 2 Weeks A-1 pH 6.0 + 23.9 2 pH 7.0 + 63.7 3 pH 8.0 - 98.6 4 pH 9.0 - 99.4 3 Weeks A-1 ph 6.0 + 19.3 2 pH 7.0 + 54.2 3 pH 8.0 - 98.0 4 pH 9.0 - 99.0 ______________________________________ Note: The symbol "-" denotes that change in appearance was not observed. The symbol "+" denotes that change in appearance was observed. (hereinafter, the same as above)
TABLE 9 ______________________________________ Formula 1 Week 2 Weeks 4 Weeks ______________________________________ B-1 - - - B-2 - - + ______________________________________
TABLE 10
______________________________________
Formula Residue (%)
Appearance
______________________________________
B-1 93.4 +
B-3 100.9 -
______________________________________
TABLE 11
______________________________________
Appearance
Residue (%)
______________________________________
Example 6 - 100.9
Example 7 - 99.2
Example 8 - 98.9
______________________________________
Claims (9)
1. A locally administrable opthalmic, otic or nasal therapeutic composition for the treatment of inflammatory disease of the eye, ear or nasal passage which comprises an anti-inflammatory effective amount of a benzoylphenylacetic acid of the formula ##STR3## wherein R is hydrogen or a halogen atom or a pharmaceutically acceptable salt thereof or a hydrate of said acid or salt in admixture with
(a) an isotonizing agent, and
(b) at least one member of the group consisting of a microbial agent and a preservative.
2. The locally administrable therapeutic composition for inflammatory disease according to claim 1, wherein the water-soluble polymer is polyvinyl pyrrolidone, polyvinyl alcohol, carboxypropylcellulose, hydroxyethylcellulose, hydroxypropylcellulose or sodium salt of polyacrylic acid.
3. The locally administrable therapeutic composition for inflammatory disease according to claim 1, wherein the concentration of the water-soluble polymer is in the range of about 0.1-10 W/W %.
4. The locally administrable therapeutic composition for inflammatory disease according to claim 1, wherein the sulfite is in the form of sodium, potassium, calcium or magnesium salt.
5. The locally administrable therapeutic composition for inflammatory disease according to claim 1, wherein the concentration of the sulfite is in the range of about 0.1-1 W/W %.
6. A composition according to claim 1 in the form of an aqueous solution.
7. A method of treating animals or humans to alleviate inflammation of the eye, nasal passage or ear canal which comprises applying to the eye, nasal passage or ear canal an anti-inflammatory effective amount of a compound of the formula: ##STR4## wherein R is hydrogen or a halogen atom or a pharmaceutically acceptable salt thereof, or a hydrate of said acid or salt, as active ingredient.
8. In a locally administrable stable aqueous therapeutic composition for use in the treatment of inflammatory disease comprising an anti-inflammatory effective amount of a benzoylphenylacetic acid of the formula ##STR5## wherein R is hydrogen or a halogen atom, or a pharmaceutically acceptable salt thereof, or a hydrate of said acid or salt, the improvement wherein said composition contains a stabilizing amount of a water-soluble polymer and a sulfite, the pH of said composition being in the range of about 6-9.
9. A locally administrable opthalmic ointment for the treatment of inflammatory disease of the eye which comprises an anti-inflammatory effective amount of a benzoylphenylacetic acid of the formula ##STR6## wherein R is hydrogen or a halogen atom or a pharmaceutically acceptable salt thereof or a hydrate of said acid or salt in admixture with an eye ointment base.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1668388 | 1988-01-27 | ||
| JP63-16683 | 1988-01-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US4910225A true US4910225A (en) | 1990-03-20 |
Family
ID=11923115
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US07/301,033 Expired - Lifetime US4910225A (en) | 1988-01-27 | 1989-01-24 | Locally administrable therapeutic composition for inflammatory disease |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US4910225A (en) |
| EP (1) | EP0326915B1 (en) |
| JP (1) | JP2683676B2 (en) |
| KR (1) | KR960005707B1 (en) |
| AT (1) | ATE80043T1 (en) |
| AU (1) | AU609932B2 (en) |
| CA (1) | CA1325382C (en) |
| DE (1) | DE68902649T2 (en) |
| ES (1) | ES2052784T3 (en) |
| GR (1) | GR3005586T3 (en) |
| HK (1) | HK162895A (en) |
| PH (1) | PH26827A (en) |
Cited By (48)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5475034A (en) * | 1994-06-06 | 1995-12-12 | Alcon Laboratories, Inc. | Topically administrable compositions containing 3-benzoylphenylacetic acid derivatives for treatment of ophthalmic inflammatory disorders |
| US5895645A (en) * | 1995-01-31 | 1999-04-20 | Bausch & Lomb Incorporated | Opthalmic solution for artificial tears |
| US6316483B1 (en) | 1994-02-03 | 2001-11-13 | Schering Corporation | Oxymetazoline HCI and/or chlorpheniramine maleate nasal spray compositions |
| US20030187072A1 (en) * | 2003-02-14 | 2003-10-02 | Kapin Michael A. | Method of treating angiogenesis-related disorders |
| US20030199509A1 (en) * | 2002-04-19 | 2003-10-23 | Chin-Ming Chang | Combination of brimonidine and timolol for topical ophthalmic use |
| US6638976B2 (en) | 2000-08-14 | 2003-10-28 | Alcon, Inc. | Method of treating neurodegenerative disorders of the retina and optic nerve head |
| US20030207941A1 (en) * | 2002-05-03 | 2003-11-06 | Bingaman David P. | Method of treating vascular endothelial growth factor mediated vascular disorders |
| US6646003B2 (en) | 2001-04-02 | 2003-11-11 | Alcon, Inc. | Method of treating ocular inflammatory and angiogenesis-related disorders of the posterior segment of the eye using an amide derivative of flurbiprofen or ketorolac |
| US20040259765A1 (en) * | 2003-06-13 | 2004-12-23 | Bingaman David P. | Formulations of non-steroidal anti-inflammatory agents to treat pathologic ocular angiogenesis |
| US20050239895A1 (en) * | 2003-01-21 | 2005-10-27 | Shirou Sawa | Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
| US20060122277A1 (en) * | 2004-12-02 | 2006-06-08 | Alcon, Inc. | Topical nepafenac formulations |
| US20060257486A1 (en) * | 2005-05-10 | 2006-11-16 | Alcon, Inc. | Suspension formulations of nepafenac and other ophthalmic drugs for topical treatment of ophthalmic disorders |
| US20060257487A1 (en) * | 2005-05-10 | 2006-11-16 | Alcon, Inc. | Suspension formulations of nepafenac and other ophthalmic drugs for topical treatment of ophthalmic disorders |
| US20070021507A1 (en) * | 2004-11-05 | 2007-01-25 | Shirou Sawa | Aqueous eye drops with accelerated intraocular migration |
| US20070082857A1 (en) * | 2003-11-14 | 2007-04-12 | Shirou Sawa | Aqueous solution preparation containing aminoglycoside antibiotic and bromfenac |
| US20070254841A1 (en) * | 2006-01-25 | 2007-11-01 | Ophthalmic Research Associates, Inc. | Formulations and methods for treating dry eye |
| US20070254939A1 (en) * | 2006-04-28 | 2007-11-01 | Alcon, Inc. | Formulations Containing Amide Derivatives of Carboxylic Acid NSAIDS for Topical Administration to the Eye |
| US20080153818A1 (en) * | 2006-12-21 | 2008-06-26 | Bingaman David P | Methods for preventing inflammation during surgery |
| US20080153819A1 (en) * | 2006-12-21 | 2008-06-26 | Bingaman David P | Methods for treating macular edema and pathologic ocular angiogenesis using a neuroprotective agent and a receptor tyrosine kinase inhibitor |
| US20080274191A1 (en) * | 2004-10-20 | 2008-11-06 | Interpharm Development Sa | Bioadhesive Composition With Programmed Release |
| US20080275122A1 (en) * | 2007-05-01 | 2008-11-06 | Alcon Research, Ltd. | N-halogenated amino acid formulations with anti-inflammatory compounds |
| US20090010850A1 (en) * | 2007-05-24 | 2009-01-08 | Ousler Iii George W | Formulations and methods for treating dry eye |
| US20090105245A1 (en) * | 2006-12-21 | 2009-04-23 | Bingaman David P | Methods for treating macular edema and ocular angiogenesis using an anti-inflammatory agent and a receptor tyrosine kinase inhibitor |
| US20100130580A1 (en) * | 2006-01-25 | 2010-05-27 | Aciex Therapeutics, Inc. | Formulations and Methods for Treating Dry Eye |
| US20100227928A1 (en) * | 2009-03-05 | 2010-09-09 | Kamran Hosseini | Non-steroidal anti-inflammatory ophthalmic compositions |
| US20110054031A1 (en) * | 2008-02-21 | 2011-03-03 | Ista Pharmaceuticals, Inc. | Ophthalmic NSAIDS as Adjuvants |
| EP2311794A2 (en) | 2009-10-15 | 2011-04-20 | Johnson Matthey Public Limited Company | Polymorphs of bromfenac sodium and methods for preparing bromfenec sodium polymorphs |
| US20110092596A1 (en) * | 2009-10-15 | 2011-04-21 | Johnson Matthey Public Limited Company | Polymorphs of bromfenac sodium and methods for preparing bromfenac sodium polymorphs |
| WO2014078766A1 (en) | 2012-11-19 | 2014-05-22 | Bausch & Lomb Incorporated | Aqueous liquid composition containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
| WO2014204952A1 (en) | 2013-06-19 | 2014-12-24 | Sentiss Research Center | Stable bromfenac solution |
| US9056057B2 (en) | 2012-05-03 | 2015-06-16 | Kala Pharmaceuticals, Inc. | Nanocrystals, compositions, and methods that aid particle transport in mucus |
| WO2015087267A2 (en) | 2013-12-12 | 2015-06-18 | Sentiss Pharma Private Limited | Stable bromfenac ophthalmic solution |
| US9107888B2 (en) | 2011-01-18 | 2015-08-18 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid bromfenac composition having preservative efficacy |
| US9353122B2 (en) | 2013-02-15 | 2016-05-31 | Kala Pharmaceuticals, Inc. | Therapeutic compounds and uses thereof |
| US9353123B2 (en) | 2013-02-20 | 2016-05-31 | Kala Pharmaceuticals, Inc. | Therapeutic compounds and uses thereof |
| US9522153B2 (en) | 2009-12-22 | 2016-12-20 | Allergan, Inc. | Compositions and methods for lowering intraocular pressure |
| CN106404952A (en) * | 2016-08-31 | 2017-02-15 | 辰欣佛都药业（汶上）有限公司 | Determination method for related substances of Bromfenac sodium eye drops |
| US9688688B2 (en) | 2013-02-20 | 2017-06-27 | Kala Pharmaceuticals, Inc. | Crystalline forms of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one and uses thereof |
| US9790232B2 (en) | 2013-11-01 | 2017-10-17 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| US9827191B2 (en) | 2012-05-03 | 2017-11-28 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
| US9890173B2 (en) | 2013-11-01 | 2018-02-13 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| US10253036B2 (en) | 2016-09-08 | 2019-04-09 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| US10336767B2 (en) | 2016-09-08 | 2019-07-02 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| US10392399B2 (en) | 2016-09-08 | 2019-08-27 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| US10688041B2 (en) | 2012-05-03 | 2020-06-23 | Kala Pharmaceuticals, Inc. | Compositions and methods utilizing poly(vinyl alcohol) and/or other polymers that aid particle transport in mucus |
| US11219597B2 (en) | 2012-05-03 | 2022-01-11 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
| WO2022092868A1 (en) | 2020-10-29 | 2022-05-05 | 주식회사태준제약 | Ophthalmic composition |
| WO2022158893A2 (en) | 2021-01-21 | 2022-07-28 | 주식회사태준제약 | Ophthalmic composition |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR020661A1 (en) * | 1998-09-30 | 2002-05-22 | Alcon Lab Inc | A PHARMACEUTICAL COMPOSITION TOPICA OFTALMICA, OTICA OR NASAL AND THE USE OF THE SAME FOR THE MANUFACTURE OF A MEDICINAL PRODUCT |
| DE19961307A1 (en) * | 1999-12-18 | 2001-07-12 | Krewel Meuselbach Gmbh | Medical device for moisturizing and cleaning the nasal mucosa |
| AR030345A1 (en) * | 2000-08-14 | 2003-08-20 | Alcon Inc | METHOD OF TREATMENT OF DISORDERS RELATED TO ANGIOGENESIS |
| CN111712238A (en) * | 2017-12-14 | 2020-09-25 | 参天制药株式会社 | Eye drops containing 2-amino-3- (4-bromobenzoyl) phenylacetic acid or its salt |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4045576A (en) * | 1975-08-13 | 1977-08-30 | A. H. Robins Company, Incorporated | Anti-inflammatory methods using 2-amino-3-(5- and 6-)benzoylphenylacetic acids, esters and metal salts thereof and the compounds |
| JPS58201710A (en) * | 1982-05-18 | 1983-11-24 | Meiji Seika Kaisha Ltd | Anti-inflammatory paste preparation for oral cavity |
| US4568695A (en) * | 1983-12-07 | 1986-02-04 | A. H. Robins Company, Incorporated | 2-Amino-3-benzoyl-phenethylalcohols and intermediates therefor |
| EP0221753A2 (en) * | 1985-10-28 | 1987-05-13 | A.H. ROBINS COMPANY, INCORPORATED (a Delaware corporation) | Transdermal treatment for pain and inflammation with 2-amino-3-aroylbenzeneacetic acids, salts and esters |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU512570B2 (en) * | 1975-08-13 | 1980-10-16 | A.H. Robins Company, Incorporated | Amino benzophenones |
-
1989
- 1989-01-24 CA CA000589025A patent/CA1325382C/en not_active Expired - Lifetime
- 1989-01-24 US US07/301,033 patent/US4910225A/en not_active Expired - Lifetime
- 1989-01-25 ES ES89101237T patent/ES2052784T3/en not_active Expired - Lifetime
- 1989-01-25 EP EP89101237A patent/EP0326915B1/en not_active Expired - Lifetime
- 1989-01-25 AT AT89101237T patent/ATE80043T1/en not_active IP Right Cessation
- 1989-01-25 AU AU28786/89A patent/AU609932B2/en not_active Expired
- 1989-01-25 DE DE8989101237T patent/DE68902649T2/en not_active Expired - Lifetime
- 1989-01-26 PH PH38108A patent/PH26827A/en unknown
- 1989-01-27 JP JP1018549A patent/JP2683676B2/en not_active Expired - Lifetime
- 1989-01-27 KR KR1019890000892A patent/KR960005707B1/en not_active IP Right Cessation
-
1992
- 1992-09-03 GR GR920401848T patent/GR3005586T3/el unknown
-
1995
- 1995-10-19 HK HK162895A patent/HK162895A/en not_active IP Right Cessation
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4045576A (en) * | 1975-08-13 | 1977-08-30 | A. H. Robins Company, Incorporated | Anti-inflammatory methods using 2-amino-3-(5- and 6-)benzoylphenylacetic acids, esters and metal salts thereof and the compounds |
| US4126635A (en) * | 1975-08-13 | 1978-11-21 | A. H. Robins Company, Incorporated | 2-amino-3-(5- and 6-)benzoylphenylacetic acids, esters and metal salts thereof |
| JPS58201710A (en) * | 1982-05-18 | 1983-11-24 | Meiji Seika Kaisha Ltd | Anti-inflammatory paste preparation for oral cavity |
| US4568695A (en) * | 1983-12-07 | 1986-02-04 | A. H. Robins Company, Incorporated | 2-Amino-3-benzoyl-phenethylalcohols and intermediates therefor |
| EP0221753A2 (en) * | 1985-10-28 | 1987-05-13 | A.H. ROBINS COMPANY, INCORPORATED (a Delaware corporation) | Transdermal treatment for pain and inflammation with 2-amino-3-aroylbenzeneacetic acids, salts and esters |
| US4683242A (en) * | 1985-10-28 | 1987-07-28 | A. H. Robins Company, Incorporated | Transdermal treatment for pain and inflammation with 2-amino-3-aroylbenzeneacetic acids, salts and esters |
Non-Patent Citations (4)
| Title |
|---|
| Chem. Abst. 107 (1987) 211870z. * |
| Chem. Abst. 107-(1987)-211870z. |
| Walsh et al., Journal of Medicinal Chemistry, 1989, vol. 27, No. 11, pp. 1379 1388. * |
| Walsh et al., Journal of Medicinal Chemistry, 1989, vol. 27, No. 11, pp. 1379-1388. |
Cited By (131)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6316483B1 (en) | 1994-02-03 | 2001-11-13 | Schering Corporation | Oxymetazoline HCI and/or chlorpheniramine maleate nasal spray compositions |
| US6824762B2 (en) | 1994-02-03 | 2004-11-30 | Schering-Plough Healthcare Products Inc. | Nasal spray compositions |
| WO1995033457A1 (en) * | 1994-06-06 | 1995-12-14 | Alcon Laboratories, Inc. | Topically administrable compositions containing 3-benzoylphenylacetic acid derivatives for treatment of ophthalmic inflammatory disorders |
| US5475034A (en) * | 1994-06-06 | 1995-12-12 | Alcon Laboratories, Inc. | Topically administrable compositions containing 3-benzoylphenylacetic acid derivatives for treatment of ophthalmic inflammatory disorders |
| US5895645A (en) * | 1995-01-31 | 1999-04-20 | Bausch & Lomb Incorporated | Opthalmic solution for artificial tears |
| US6638976B2 (en) | 2000-08-14 | 2003-10-28 | Alcon, Inc. | Method of treating neurodegenerative disorders of the retina and optic nerve head |
| US6646003B2 (en) | 2001-04-02 | 2003-11-11 | Alcon, Inc. | Method of treating ocular inflammatory and angiogenesis-related disorders of the posterior segment of the eye using an amide derivative of flurbiprofen or ketorolac |
| US20080132512A1 (en) * | 2002-04-19 | 2008-06-05 | Allergan, Inc. | Combination of Brimonidine and Timolol for Topical Ophthalmic Use |
| US8748425B2 (en) | 2002-04-19 | 2014-06-10 | Allergan Sales, Llc | Combination of brimonidine and timolol for topical ophthalmic use |
| US20030199509A1 (en) * | 2002-04-19 | 2003-10-23 | Chin-Ming Chang | Combination of brimonidine and timolol for topical ophthalmic use |
| US9474751B1 (en) | 2002-04-19 | 2016-10-25 | Allergan Sales, Llc | Combination of brimonidine and timolol for topical ophthalmic use |
| US8133890B2 (en) | 2002-04-19 | 2012-03-13 | Allergan, Inc. | Combination of brimonidine and timolol for topical ophthalmic use |
| US8354409B2 (en) | 2002-04-19 | 2013-01-15 | Allergan, Inc. | Combination of brimonidine and timolol for topical ophthalmic use |
| US7030149B2 (en) * | 2002-04-19 | 2006-04-18 | Allergan, Inc. | Combination of brimonidine timolol for topical ophthalmic use |
| US9770453B2 (en) | 2002-04-19 | 2017-09-26 | Allergan Sales, Llc | Combination of brimonidine and timolol for topical ophthalmic use |
| US9907802B1 (en) | 2002-04-19 | 2018-03-06 | Allergan Sales, Llc | Combination of brimonidine and timolol for topical ophthalmic use |
| US9907801B1 (en) | 2002-04-19 | 2018-03-06 | Allergan Sales, Llc | Combination of brimonidine and timolol for topical ophthalmic use |
| US20030207941A1 (en) * | 2002-05-03 | 2003-11-06 | Bingaman David P. | Method of treating vascular endothelial growth factor mediated vascular disorders |
| US20050143468A1 (en) * | 2002-05-03 | 2005-06-30 | Bingaman David P. | Method of treating vascular endothelial growth factor mediated vascular disorders |
| CN100341498C (en) * | 2003-01-21 | 2007-10-10 | 千寿制药株式会社 | Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
| US9144609B2 (en) | 2003-01-21 | 2015-09-29 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
| US8927606B1 (en) | 2003-01-21 | 2015-01-06 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
| US8871813B2 (en) | 2003-01-21 | 2014-10-28 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
| US20070287749A1 (en) * | 2003-01-21 | 2007-12-13 | Ista Pharmaceuticals, Inc. | Bromfenac ophthalmic formulations and methods of use |
| US8129431B2 (en) | 2003-01-21 | 2012-03-06 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
| US8754131B2 (en) | 2003-01-21 | 2014-06-17 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
| US8669290B2 (en) * | 2003-01-21 | 2014-03-11 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
| US8497304B2 (en) | 2003-01-21 | 2013-07-30 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
| US20130090384A1 (en) * | 2003-01-21 | 2013-04-11 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
| US20050239895A1 (en) * | 2003-01-21 | 2005-10-27 | Shirou Sawa | Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
| US9561277B2 (en) | 2003-01-21 | 2017-02-07 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid preparation containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
| US20030187072A1 (en) * | 2003-02-14 | 2003-10-02 | Kapin Michael A. | Method of treating angiogenesis-related disorders |
| US20070043006A1 (en) * | 2003-06-13 | 2007-02-22 | Bingaman David P | Formulations of non-steroidal anti-inflammatory agents to treat pathologic ocular angiogenesis |
| US20040259765A1 (en) * | 2003-06-13 | 2004-12-23 | Bingaman David P. | Formulations of non-steroidal anti-inflammatory agents to treat pathologic ocular angiogenesis |
| US7829544B2 (en) | 2003-11-14 | 2010-11-09 | Senju Pharmaceutical Co., Ltd. | Aqueous solution preparation containing aminoglycoside antibiotic and bromfenac |
| US20070082857A1 (en) * | 2003-11-14 | 2007-04-12 | Shirou Sawa | Aqueous solution preparation containing aminoglycoside antibiotic and bromfenac |
| US20080274191A1 (en) * | 2004-10-20 | 2008-11-06 | Interpharm Development Sa | Bioadhesive Composition With Programmed Release |
| US20160235715A1 (en) * | 2004-10-20 | 2016-08-18 | Care & Pharma Perspectives Sa | Pasty Bio-Adhesive Sustained Release Compositions |
| US10646435B2 (en) * | 2004-10-20 | 2020-05-12 | Care & Pharma Perspectives Sa | Pasty bio-adhesive sustained release compositions |
| KR101312740B1 (en) * | 2004-11-05 | 2013-09-27 | 센주 세이야꾸 가부시키가이샤 | Aqueous eye drops with accelerated intraocular migration |
| US8518996B2 (en) | 2004-11-05 | 2013-08-27 | Senju Pharmaceutical Co., Ltd. | Aqueous intraocular penetration-promoting eye drop |
| CN1993118B (en) * | 2004-11-05 | 2010-06-16 | 千寿制药株式会社 | Aqueous eye drops with accelerated intraocular migration permeability |
| US20070021507A1 (en) * | 2004-11-05 | 2007-01-25 | Shirou Sawa | Aqueous eye drops with accelerated intraocular migration |
| US8299124B2 (en) | 2004-11-05 | 2012-10-30 | Senju Pharmaceutical Co., Ltd. | Aqueous intraocular penetration-promoting eye drop |
| US7834059B2 (en) | 2004-12-02 | 2010-11-16 | Alcon, Inc. | Topical nepafenac formulations |
| US20060122277A1 (en) * | 2004-12-02 | 2006-06-08 | Alcon, Inc. | Topical nepafenac formulations |
| US8324281B2 (en) | 2004-12-02 | 2012-12-04 | Novartis Ag | Topical nepafenac formulations |
| US8071648B2 (en) | 2004-12-02 | 2011-12-06 | Novartis Ag | Topical nepafenac formulations |
| US20060257487A1 (en) * | 2005-05-10 | 2006-11-16 | Alcon, Inc. | Suspension formulations of nepafenac and other ophthalmic drugs for topical treatment of ophthalmic disorders |
| US20060257486A1 (en) * | 2005-05-10 | 2006-11-16 | Alcon, Inc. | Suspension formulations of nepafenac and other ophthalmic drugs for topical treatment of ophthalmic disorders |
| US20070254841A1 (en) * | 2006-01-25 | 2007-11-01 | Ophthalmic Research Associates, Inc. | Formulations and methods for treating dry eye |
| US20100130580A1 (en) * | 2006-01-25 | 2010-05-27 | Aciex Therapeutics, Inc. | Formulations and Methods for Treating Dry Eye |
| US20070254939A1 (en) * | 2006-04-28 | 2007-11-01 | Alcon, Inc. | Formulations Containing Amide Derivatives of Carboxylic Acid NSAIDS for Topical Administration to the Eye |
| US20080153819A1 (en) * | 2006-12-21 | 2008-06-26 | Bingaman David P | Methods for treating macular edema and pathologic ocular angiogenesis using a neuroprotective agent and a receptor tyrosine kinase inhibitor |
| US20090105245A1 (en) * | 2006-12-21 | 2009-04-23 | Bingaman David P | Methods for treating macular edema and ocular angiogenesis using an anti-inflammatory agent and a receptor tyrosine kinase inhibitor |
| US20080153818A1 (en) * | 2006-12-21 | 2008-06-26 | Bingaman David P | Methods for preventing inflammation during surgery |
| US20080275122A1 (en) * | 2007-05-01 | 2008-11-06 | Alcon Research, Ltd. | N-halogenated amino acid formulations with anti-inflammatory compounds |
| US20100210730A1 (en) * | 2007-05-01 | 2010-08-19 | Alcon Research, Ltd. | N-halogenated amino acid formulations with anti-inflammatory compounds |
| US20090010850A1 (en) * | 2007-05-24 | 2009-01-08 | Ousler Iii George W | Formulations and methods for treating dry eye |
| US20110054031A1 (en) * | 2008-02-21 | 2011-03-03 | Ista Pharmaceuticals, Inc. | Ophthalmic NSAIDS as Adjuvants |
| US8778999B2 (en) | 2009-03-05 | 2014-07-15 | Insite Vision Incorporated | Non-steroidal anti-inflammatory ophthalmic compositions |
| EP2403493A4 (en) * | 2009-03-05 | 2013-09-18 | Insite Vision Inc | Non-steroidal anti-inflammatory ophthalmic compositions |
| US20100227928A1 (en) * | 2009-03-05 | 2010-09-09 | Kamran Hosseini | Non-steroidal anti-inflammatory ophthalmic compositions |
| EP2403493A2 (en) * | 2009-03-05 | 2012-01-11 | Insite Vision Incorporated | Non-steroidal anti-inflammatory ophthalmic compositions |
| US20110092596A1 (en) * | 2009-10-15 | 2011-04-21 | Johnson Matthey Public Limited Company | Polymorphs of bromfenac sodium and methods for preparing bromfenac sodium polymorphs |
| US9061968B2 (en) | 2009-10-15 | 2015-06-23 | Johnson Matthey Public Limited Company | Polymorphs of bromfenac sodium and methods for preparing bromfenac sodium polymorphs |
| US9914697B2 (en) | 2009-10-15 | 2018-03-13 | Johnson Matthey Public Limited Company | Methods for making polymorphs of bromfenac sodium and bromfenac sodium formulations |
| US9216947B2 (en) | 2009-10-15 | 2015-12-22 | Johnson Matthey Public Limited Company | Polymorphs of bromfenac sodium and methods for preparing bromfenac sodium polymorphs |
| US8481780B2 (en) | 2009-10-15 | 2013-07-09 | Johnson Matthey Public Limited Company | Polymorphs of bromfenac sodium and methods for preparing bromfenac sodium polymorphs |
| US8299295B2 (en) | 2009-10-15 | 2012-10-30 | Johnson Matthey Public Limited Company | Polymorphs of bromfenac sodium and methods for preparing bromfenac sodium polymorphs |
| EP2311794A2 (en) | 2009-10-15 | 2011-04-20 | Johnson Matthey Public Limited Company | Polymorphs of bromfenac sodium and methods for preparing bromfenec sodium polymorphs |
| US9045388B2 (en) | 2009-10-15 | 2015-06-02 | Johnson Matthey Public Limited Company | Polymorphs of bromfenac sodium and methods for preparing bromfenac sodium polymorphs |
| US9801891B2 (en) | 2009-12-22 | 2017-10-31 | Allergan, Inc. | Compositions and methods for lowering intraocular pressure |
| US9522153B2 (en) | 2009-12-22 | 2016-12-20 | Allergan, Inc. | Compositions and methods for lowering intraocular pressure |
| US9107888B2 (en) | 2011-01-18 | 2015-08-18 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid bromfenac composition having preservative efficacy |
| US9561280B2 (en) | 2011-01-18 | 2017-02-07 | Senju Pharmaceutical Co., Ltd. | Aqueous liquid bromfenac composition having preservative efficacy |
| US9056057B2 (en) | 2012-05-03 | 2015-06-16 | Kala Pharmaceuticals, Inc. | Nanocrystals, compositions, and methods that aid particle transport in mucus |
| US11219596B2 (en) | 2012-05-03 | 2022-01-11 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
| US9393213B2 (en) | 2012-05-03 | 2016-07-19 | Kala Pharmaceuticals, Inc. | Nanocrystals, compositions, and methods that aid particle transport in mucus |
| US12115246B2 (en) | 2012-05-03 | 2024-10-15 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
| US11878072B2 (en) | 2012-05-03 | 2024-01-23 | Alcon Inc. | Compositions and methods utilizing poly(vinyl alcohol) and/or other polymers that aid particle transport in mucus |
| US9737491B2 (en) | 2012-05-03 | 2017-08-22 | The Johns Hopkins University | Nanocrystals, compositions, and methods that aid particle transport in mucus |
| US9393212B2 (en) | 2012-05-03 | 2016-07-19 | Kala Pharmaceuticals, Inc. | Nanocrystals, compositions, and methods that aid particle transport in mucus |
| US11872318B2 (en) | 2012-05-03 | 2024-01-16 | The Johns Hopkins University | Nanocrystals, compositions, and methods that aid particle transport in mucus |
| US11642317B2 (en) | 2012-05-03 | 2023-05-09 | The Johns Hopkins University | Nanocrystals, compositions, and methods that aid particle transport in mucus |
| US11318088B2 (en) | 2012-05-03 | 2022-05-03 | Kala Pharmaceuticals, Inc. | Compositions and methods utilizing poly(vinyl alcohol) and/or other polymers that aid particle transport in mucus |
| US9827191B2 (en) | 2012-05-03 | 2017-11-28 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
| US10646437B2 (en) | 2012-05-03 | 2020-05-12 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
| US11219597B2 (en) | 2012-05-03 | 2022-01-11 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
| US10993908B2 (en) | 2012-05-03 | 2021-05-04 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
| US10945948B2 (en) | 2012-05-03 | 2021-03-16 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
| US9532955B2 (en) | 2012-05-03 | 2017-01-03 | Kala Pharmaceuticals, Inc. | Nanocrystals, compositions, and methods that aid particle transport in mucus |
| US10857096B2 (en) | 2012-05-03 | 2020-12-08 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
| US10736854B2 (en) | 2012-05-03 | 2020-08-11 | The Johns Hopkins University | Nanocrystals, compositions, and methods that aid particle transport in mucus |
| US10688045B2 (en) | 2012-05-03 | 2020-06-23 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
| US10688041B2 (en) | 2012-05-03 | 2020-06-23 | Kala Pharmaceuticals, Inc. | Compositions and methods utilizing poly(vinyl alcohol) and/or other polymers that aid particle transport in mucus |
| US10646436B2 (en) | 2012-05-03 | 2020-05-12 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
| WO2014078766A1 (en) | 2012-11-19 | 2014-05-22 | Bausch & Lomb Incorporated | Aqueous liquid composition containing 2-amino-3-(4-bromobenzoyl)phenylacetic acid |
| US9353122B2 (en) | 2013-02-15 | 2016-05-31 | Kala Pharmaceuticals, Inc. | Therapeutic compounds and uses thereof |
| US10966987B2 (en) | 2013-02-15 | 2021-04-06 | Kala Pharmaceuticals, Inc. | Therapeutic compounds and uses thereof |
| US10398703B2 (en) | 2013-02-15 | 2019-09-03 | Kala Pharmaceuticals, Inc. | Therapeutic compounds and uses thereof |
| US9827248B2 (en) | 2013-02-15 | 2017-11-28 | Kala Pharmaceuticals, Inc. | Therapeutic compounds and uses thereof |
| US9877970B2 (en) | 2013-02-15 | 2018-01-30 | Kala Pharmaceuticals, Inc. | Therapeutic compounds and uses thereof |
| US11369611B2 (en) | 2013-02-20 | 2022-06-28 | Kala Pharmaceuticals, Inc. | Therapeutic compounds and uses thereof |
| US9353123B2 (en) | 2013-02-20 | 2016-05-31 | Kala Pharmaceuticals, Inc. | Therapeutic compounds and uses thereof |
| US10285991B2 (en) | 2013-02-20 | 2019-05-14 | Kala Pharmaceuticals, Inc. | Therapeutic compounds and uses thereof |
| US9833453B2 (en) | 2013-02-20 | 2017-12-05 | Kala Pharmaceuticals, Inc. | Therapeutic compounds and uses thereof |
| US9861634B2 (en) | 2013-02-20 | 2018-01-09 | Kala Pharmaceuticals, Inc. | Therapeutic compounds and uses thereof |
| US10758539B2 (en) | 2013-02-20 | 2020-09-01 | Kala Pharmaceuticals, Inc. | Therapeutic compounds and uses thereof |
| US9688688B2 (en) | 2013-02-20 | 2017-06-27 | Kala Pharmaceuticals, Inc. | Crystalline forms of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one and uses thereof |
| WO2014204952A1 (en) | 2013-06-19 | 2014-12-24 | Sentiss Research Center | Stable bromfenac solution |
| US9890173B2 (en) | 2013-11-01 | 2018-02-13 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| US10618906B2 (en) | 2013-11-01 | 2020-04-14 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| US9790232B2 (en) | 2013-11-01 | 2017-10-17 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| US10975090B2 (en) | 2013-11-01 | 2021-04-13 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| US11713323B2 (en) | 2013-11-01 | 2023-08-01 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| US10160765B2 (en) | 2013-11-01 | 2018-12-25 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| WO2015087267A2 (en) | 2013-12-12 | 2015-06-18 | Sentiss Pharma Private Limited | Stable bromfenac ophthalmic solution |
| CN106404952B (en) * | 2016-08-31 | 2019-06-11 | 辰欣佛都药业（汶上）有限公司 | A kind of measuring method of the sodium bromophenolate eye drops in relation to substance |
| CN106404952A (en) * | 2016-08-31 | 2017-02-15 | 辰欣佛都药业（汶上）有限公司 | Determination method for related substances of Bromfenac sodium eye drops |
| US11021487B2 (en) | 2016-09-08 | 2021-06-01 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| US10392399B2 (en) | 2016-09-08 | 2019-08-27 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| US11104685B2 (en) | 2016-09-08 | 2021-08-31 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| US10626121B2 (en) | 2016-09-08 | 2020-04-21 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| US10336767B2 (en) | 2016-09-08 | 2019-07-02 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| US10766907B2 (en) | 2016-09-08 | 2020-09-08 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| US10253036B2 (en) | 2016-09-08 | 2019-04-09 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| WO2022092868A1 (en) | 2020-10-29 | 2022-05-05 | 주식회사태준제약 | Ophthalmic composition |
| KR20220057465A (en) | 2020-10-29 | 2022-05-09 | 주식회사태준제약 | Ophthalmic Composition |
| KR20220104114A (en) | 2020-10-29 | 2022-07-26 | 주식회사태준제약 | Ophthalmic Composition |
| WO2022158893A2 (en) | 2021-01-21 | 2022-07-28 | 주식회사태준제약 | Ophthalmic composition |
Also Published As
| Publication number | Publication date |
|---|---|
| CA1325382C (en) | 1993-12-21 |
| ATE80043T1 (en) | 1992-09-15 |
| JPH02124817A (en) | 1990-05-14 |
| KR960005707B1 (en) | 1996-05-01 |
| DE68902649D1 (en) | 1992-10-08 |
| KR890011823A (en) | 1989-08-22 |
| JP2683676B2 (en) | 1997-12-03 |
| PH26827A (en) | 1992-11-05 |
| EP0326915B1 (en) | 1992-09-02 |
| GR3005586T3 (en) | 1993-06-07 |
| AU2878689A (en) | 1989-07-27 |
| EP0326915A1 (en) | 1989-08-09 |
| ES2052784T3 (en) | 1994-07-16 |
| HK162895A (en) | 1995-10-27 |
| AU609932B2 (en) | 1991-05-09 |
| DE68902649T2 (en) | 1993-02-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4910225A (en) | Locally administrable therapeutic composition for inflammatory disease | |
| US5610184A (en) | Method for sustained and extended corneal analgesia | |
| US4454151A (en) | Use of pyrrolo pyrroles in treatment of ophthalmic diseases | |
| US4474811A (en) | Anti-inflammatory ophthalmic solution and process for preparing the same | |
| US4599360A (en) | Ophthalmic anti-inflammatory agents | |
| US5663205A (en) | Pharmaceutical composition for use in glaucoma treatment | |
| EP0235544B1 (en) | Ocular antihypertensive composition for topical use | |
| US10973758B2 (en) | Methods of eye treatment using therapeutic compositions containing dipyridamole | |
| US5438060A (en) | Method of reducing elevated intraocular pressure | |
| US5198454A (en) | Use of OB-104 to treat ocular inflammation | |
| US5270050A (en) | Paracetamol-based pharmaceutical composition | |
| HUT70749A (en) | Anti-allergic pharmaceutical composition containing suplatast-tosilate for ophthalmic topical administracion and process for producing them | |
| US5308849A (en) | Method of reducing elevated intraocular pressure | |
| JP2530176B2 (en) | Ophthalmic composition | |
| JPH0330571B2 (en) | ||
| EP0728480A1 (en) | Use of ifenprodil for treatment of elevated intraocular pressure | |
| JPH10500130A (en) | Pharmaceutical composition for treating glaucoma containing terazosin | |
| EP0885612A1 (en) | Pirenoxine for the topical treatment of inflammatory conditions | |
| US5428030A (en) | Method of reducing elevated intraocular pressure | |
| US5240936A (en) | Treating or preventing ocular inflammation or systemic imflammatory disease | |
| JPH0797318A (en) | Intraocular pressure lowering agent containing oxyfedrine as essential component | |
| JPH09295935A (en) | Anti-opthalimic agent | |
| EP0456988A2 (en) | Use of naproxen as mydriatic agent |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AS | Assignment |
Owner name: A.H. ROBINS COMPANY, INCORPORATED, VIRGINIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:OGAWA, TAKAHIRO;KURIBAYASHI, YOSHIKAZU;USHIO, KAZUMICHI;AND OTHERS;REEL/FRAME:005034/0287 Effective date: 19890113 Owner name: SENJU PHARMACEUTICAL CO., LTD., JAPAN Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:OGAWA, TAKAHIRO;KURIBAYASHI, YOSHIKAZU;USHIO, KAZUMICHI;AND OTHERS;REEL/FRAME:005034/0287 Effective date: 19890113 |
|
| STCF | Information on status: patent grant |
Free format text: PATENTED CASE |
|
| FEPP | Fee payment procedure |
Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
| CC | Certificate of correction | ||
| FPAY | Fee payment |
Year of fee payment: 4 |
|
| FPAY | Fee payment |
Year of fee payment: 8 |
|
| FEPP | Fee payment procedure |
Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY Free format text: PAYER NUMBER DE-ASSIGNED (ORIGINAL EVENT CODE: RMPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
| FPAY | Fee payment |
Year of fee payment: 12 |